1. Field of the Invention
The present invention relates to the field of molecular biology and medicine, and more particularly to psychosis protecting (PP) nucleic acids and peptides involved in protection from psychoses and related disorders, as well as expression products, compositions thereof, and methods therefor, including detection, amplification, isolation and expression of such PP nucleic acids and PP peptides, as well as diagnostic and therapeutic methods using such PP peptides and their encoding PP nucleic acid.
2. Background of the Related Art
Psychoses, such as schizophrenia can be differentiated into two basic categories; those which are amenable to treatment, by means of conventional antipsychotic drugs, and those which are resistant to treatment, the latter usually being spoken of as "chronic" or "negative symptom" schizophrenia. Preclinical conditions of psychoses are also prevalent and could be subject to treatment if the degree of severity could be diagnosed in a standardized manner. These categories can, to some degree, be correlated with the relative balance of positive and negative symptomatology. The designation "negative (Bleulerian) symptomatology", although long known, has in recent years been used more routinely.
Treatment of psychoses and schizophrenia. Treatment of schizophrenia and other psychoses is commonly provided using the antipsychotics termed neuroleptic agents. Neuroleptic agents, regardless of their chemical structures, are pharmacologically active upon the dopamine receptor system, as dopamine antagonists. Many of these compounds, particularly the phenothiazines, also have significant activity on other neurotransmitter systems, in particular various serotonin subtypes, particularly the 5-HT-2, and on muscarinic receptors, alpha-adrenoceptors, or histamine H-1 or H-2 receptors. The clinical use of neuroleptics has provided a means for treating patients suffering from psychotic disorders, including schizophrenia. Short-term use of neuroleptics is indicated in several types of exacerbations of schizophrenia. Continuous long-term use of neuroleptics is indicated, e.g., in primary indications involving schizophrenia as well as questionable indications such as chronic characterological disorders with schizoid, "borderline," or neurotic characteristics. See, e.g., Baldessarini, Chemotherapy in Psychiatry, Revised and Enlarged Edition, Harvard University Press, Cambridge, Mass., (1985), the contents of which are entirely incorporated herein by reference.
Neuroleptics and Their Side Effects. Neuroleptics are also referred to as neuroplegics, psychoplegics, psycholeptics, antipsychotics and major tranquilizers, but are sometimes distinguished from non-neuroleptic psychotropics. Neuroleptics have also been characterized as agents that produce sedative or tranquilizing effects, and which also produce motor side effects, such as catalepsy or extrapyramidal symptomatology. Nonlimiting representative examples of neuroleptics include phenothiazine derivatives (e.g., chlorpromazine); thioxanthine derivatives (e.g., thiothixene); butyrophenone derivatives (e.g., haloperidol); dihydroindolone (e.g., molindone); dibenzoxazepine derivatives (e.g., loxapine); and "atypical" neuroleptics (e.g., sulpiride, remoxipride pimozide and clozapine). See Berstein Clinical Pharmacology Littleton, Mass.:PSG Publishing (1978); Usdin et al Clinical Pharmacology in Psychiatry New York:Elsevier North-Holland (1981); and Baldessarini, supra, (1985); which references are herein entirely incorporated by reference.
The long term use of all known anti-psychotics, including neuroleptics, has resulted in serious side effects, as set forth in Table I, such as persistent and poorly reversible motoric dysfunctions (e.g., tardive dyskinesia) in a significant number of patients. For example, classical neuroleptic agents, as exemplified by the butyrophenones and phenothiazines, can, upon long-term administration, produce severe motoric symptomatology, termed tardive dyskinesia. These motor movements are uncontrollable and can range from relatively trivial manifestations to total debilitation. Tardive dyskinesia is usually reversible upon discontinuation of the chronic neuroleptic, if the drug is discontinued soon after symptoms of tardive dyskinesia appear. Otherwise symptoms may persist. Pharmacological intervention for treatment of tardive dyskinesia is only moderately successful. Such motor abnormalities are known to occur in as high as 10% of the patients who are maintained on these drugs for several years; the incidence is much greater in certain groups, such as middle-aged females.
The following Table I presents these and additional neurological side effects of neuroleptic anti-psychotic drugs.
TABLE I __________________________________________________________________________ Neurological Side Effects of Neuroleptic-Antipsychotic Drugs Period of Reaction Features maximum risk Proposed mechanism Treatment __________________________________________________________________________ Acute dystonia Spasm of muscles of 1-5 days Dopamine excess? Antiparkinsonism agents are tongue, face, neck, Acetylcholine excess? diagnostic and curative back; may mimic (i.m. or i.v., then p.o.) seizures; not hysterical Parkinsonism Bradykinesia, rigidity, 5-30 days Dopamine blockade Antiparkinsonism agents variable tremor, mask- (rarely (p.o); dopamine agonists facies, shuffling gait persists) risky? Akathisia Motor restlessness; 5-60 days Unknown Reduce dose or change drug patient may experience (commonly low doses of propranolol;.sup.a anxiety or agitation persists) antiparkinsonism agents or or benzodiazepines may help Tardive Oral-facial dyskinesia; 6-24 months Dopamine excess? Prevention best; treatment dykinesia choreo-athetosis; some- (worse on unsatisfactory; slow spontaneous times irreversible, withdrawal) remission rarely progressive "Rabbit" Perioral tremor (late Months or Unknown Antiparkinsonism agents; reduce syndrome parkinsonism variant?); years dose of neuroleptic usually reversible Malignant Catatonia, stupor, Weeks Unknown Stop neuroleptic; antiparkinsonism syndrome fever, unstable pulse agents usually fail; bromocriptine and blood pressure; often helps; denatrolene variable; myoglobinema; can general supportive care crucial be fatal __________________________________________________________________________
In addition, clozapine, although apparently capable of producing less motor side effects, can cause irreversible, potentially fatal agranulocytosis in a minority of patients administered the drug. Such serious side effects limit the use of clozapine to patients who are resistant to treatment with other neuroleptics.
These side effects are especially prevalent in geriatric populations, and adequate pharmacological treatment of these debilitating motoric dysfunctions is not currently available. This problem has been generally associated with long-term, clinical administration of these agents, including their use in the long term treatment of schizophrenia. There is thus a great need for alternative treatments for schizophrenia, including chronic schizophrenia, without toxic side effects of known agents used for such treatment, or whose long-term administration will not produce such toxic side effects.
Treatments proposed for schizophrenia. Anti-psychotic drugs, such as neuroleptics have been found to generally affect neuroreceptors, such as dopamine and serotonin receptors. Many of these receptors have been recently cloned and sequenced, such as the serotonin 5-HT1 and 5-HT2 (see, e.g., Leonard, Int. Clin. Psychopharmacol., 7(1):13-21 (1992)) and dopamine receptors: D5 (Sunahara et al., Nature, 350:614-619 (1991)); D4 (Van Tol et al., Nature, 350:610-614 (1991)); D1 (Zhou et al., Nature, 347:76-80 (1990); Dearry et al., Nature, 347:72-76 (1990)); and rat D2 (Tourtellotte et al., Neurochem. Res., 12:565-571 (1987); Bunzow et al, Nature, 33:783-787; Miller et al, Biochem. Biophys. Res. Com., 166:109-112)).
Currently anti-psychotic agents (neuroleptics) are used for the treatment of schizophrenia and all other psychoses. Proposed treatments involve the use of compositions containing peptides and proteins which may act as ligands for receptors or portions of receptors as well as other neural active peptides and analogs thereof. Examples of such compositions include neurotensin peptide analogs (WO 93/00359, Du Pont Merck Pharmaceutical Co. (1993)), tachykinin agonists (WO 92/22569, Fujisawa Pharmaceutical Co., LTD. (1992); EP 482 539, Fujisawa Pharmaceutical Co., LTD. (1992)), galanin agonists (WO 92/20709, Astra AB (1992)), neurokinin receptor and fragments (WO 92/16547, Children's Medical Center (1992); dopamine receptor agonist/antagonist peptides (WO 91/04271, BASF AG, (1991)), thyrotropin releasing hormone analogs (U.S. Pat. No. 5,098,888, Vincent et al (1992)), enkephalin like peptides (WO 90/00564, Research Corp. Techn., Inc. (1990); U.S. Pat. Nos. 4,684,620 (1987) and 4,518,711 (1985), Hruby et al; EP 050 828, Merck, Inc. (1984)), calmodulin binding peptides (U.S. Pat. No. 5,182,262, Hruby (1993)), cerulein peptides (U.S. Pat. No. 4,552,865, Fujino et al (1985)), and dopamine releasing protein (U.S Pat. No. 5,149,786, Marcus et al. (1992)).
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of any of the claims of the present application. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.